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Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer

Published in Nature communications. 2021, vol. 12, no. 1, 7235
Abstract Developmental genes are frequently controlled by multiple enhancers sharing similar specificities. As a result, deletions of such regulatory elements have often failed to reveal their full function. Here, we use the Pitx1 testbed locus to characterize in detail the regulatory and cellular identity alterations following the deletion of one of its enhancers (Pen). By combining single cell transcriptomics and an in-embryo cell tracing approach, we observe an increased fraction of Pitx1 non/low-expressing cells and a decreased fraction of Pitx1 high-expressing cells. We find that the over-representation of Pitx1 non/low-expressing cells originates from a failure of the Pitx1 locus to coordinate enhancer activities and 3D chromatin changes. This locus mis-activation induces a localized heterochrony and a concurrent loss of irregular connective tissue, eventually leading to a clubfoot phenotype. This data suggests that, in some cases, redundant enhancers may be used to locally enforce a robust activation of their host regulatory landscapes.
Keywords AcetylationAnimalsChromatin / chemistryChromatin / metabolismConnective Tissue / growth & developmentConnective Tissue / metabolismEmbryo, MammalianEnhancer Elements, Genetic / geneticsEpigenesis, GeneticGene Expression Regulation, DevelopmentalHindlimb / cytologyHindlimb / embryologyHindlimb / metabolismLimb Buds / cytologyLimb Buds / embryologyLimb Buds / metabolismMiceModels, GeneticPaired Box Transcription Factors / geneticsPaired Box Transcription Factors / metabolismSequence Deletion
PMID: 34903763
PMCID: PMC8668926
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Article (Published version) (8.4 MB) - public document Free access
Research group Contrôle épigénétique du développement embryonnaire (999)
Swiss National Science Foundation: PP00P3_176802
(ISO format)
ROUCO, Raquel et al. Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer. In: Nature communications, 2021, vol. 12, n° 1, p. 7235. doi: 10.1038/s41467-021-27492-1 https://archive-ouverte.unige.ch/unige:159830

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Deposited on : 2022-03-24

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